Ubiquitination-mediated Regulation of Biosynthesis of the Adhesion Receptor SHPS-1 in Response to Endoplasmic Reticulum Stress

• Published in: The Journal of biological chemistry 2004-03, Vol.279 (12), p.11616-11625
• Main Authors: Murai-Takebe, Reiko, Noguchi, Tetsuya, Ogura, Takeshi, Mikami, Toshiyuki, Yanagi, Kazunori, Inagaki, Kenjiro, Ohnishi, Hiroshi, Matozaki, Takashi, Kasuga, Masato
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Antigens, Differentiation - biosynthesis; Antigens, Differentiation - genetics; Antigens, Differentiation - metabolism; Base Sequence; Cell Cycle Proteins - metabolism; Cell Line; Cysteine Endopeptidases - metabolism; DNA Primers; Endoplasmic Reticulum - metabolism; Fluorescent Antibody Technique; Membrane Glycoproteins - biosynthesis; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Molecular Sequence Data; Multienzyme Complexes - metabolism; Mutagenesis, Site-Directed; Nerve Tissue Proteins - metabolism; Neural Cell Adhesion Molecule L1 - biosynthesis; Neural Cell Adhesion Molecule L1 - genetics; Neural Cell Adhesion Molecule L1 - metabolism; Proteasome Endopeptidase Complex; Receptors, Immunologic - biosynthesis; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; S-Phase Kinase-Associated Proteins - metabolism; Ubiquitin - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M311463200

Misfolding of proteins during endoplasmic reticulum (ER) stress results in the formation of cytotoxic aggregates. The ER-associated degradation pathway counteracts such aggregation through the elimination of misfolded proteins by the ubiquitin-proteasome system. We now show that SHP substrate-1 (SHPS-1), a transmembrane glycoprotein that regulates cytoskeletal reorganization and cell-cell communication, is a physiological substrate for the Skp1-Cullin1-NFB42-Rbx1 (SCFNFB42) E3 ubiquitin ligase, a proposed mediator of ER-associated degradation. SCFNFB42 mediated the polyubiquitination of immature SHPS-1 and its degradation by the proteasome. Ectopic expression of NFB42 both suppressed the formation of aggresome-like structures and the phosphorylation of the translational regulator eIF2α induced by overproduction of SHPS-1 as well as increased the amount of mature SHPS-1 at the cell surface. An NFB42 mutant lacking the F box domain had no such effects. Our results suggest that SCFNFB42 regulates SHPS-1 biosynthesis in response to ER stress.